Congenital 17α-hydroxylase deficiency: A clinicopathologic study

Congenital 17 -Hydroxylase Deficiency: A Clinicopathologic Study HIRONOBU SASANO,MD,* TAKAYUKIMASUDA,MD,* MOTOKO OJIMA, MD,t SOITSUFUKUCHI,MD, t AND NOBUAKISASANO,MD* The histopathologic features of the adrenal glands in three cases of congenital 17o~-hydroxylase deficiency are described in relation to clinical and endocrine findings. Diffuse or nodular adrenocortical hyperplasia, particularly in the zonae fasciculata and reticularis, was observed in all cases examined. The hyperplastic adrenal cortices were composed of cells with morphologic features of hypercorticism and hyperstimulation. Myelolipomatous lesions were detected in two cases. These morphologic findings were consistent with excessive adrenocorticotropic hormone secretion in this disorder. In all the cases examined, the plasma aldosterone concentration was within normal limits, and plasma renin activity was suppressed prior to dexamethasone treatment. Morphologically, however, hyperplasia of the cells with abundant mitochondria and smooth endoplasmic reticulum seemed to involve the zona glomerulosa. Nonencapsulated nests of hypertrophied cortical cells in periadrenal tissue were remarkable in one case. From these morphologic findings, we postulated hyperfunction of the zona glomerulosa as well as involvement of corticosteroids from the zona glomeruiosa in the pathophysiology of this disorder. HUM PATHOL 18:1002--1007, 1987.

A d r e n a l 1 7 ~ - h y d r o x y l a s e deficiency results in decreased p r o d u c t i o n o f glucocorticoids a n d sex ster o i d s by the a d r e n a l c o r t e x a n d s u b s e q u e n t l y increased secretion of adrenocorticotropic h o r m o n e ( A C T H ) . T h i s A C T H excess may cause an o v e r p r o duction by the zona fasciculata o f 17-deoxycorticosteroids, including 18-hydroxy-deoxycorticosterone x,2 and 1 9 - n o r - l l - d e o x y c o r t i c o s t e r o n e ? with r e d u c e d a l d o s t e r o n e p r o d u c t i o n . T h e clinical features o f this 17e~-hydroxylase deficiency s y n d r o m e ( 1 7 a - O H D S ) are excess m i n e r a l o c o r t i c o i d activity d u e to 17-deoxycorticosteroids, e.g., high blood pressure and hypokalemia, a n d occasional h y p o g o n a d i s m b e c a u s e 1 7 a - h y d r o x y l a s e is p r e s e n t n o t o n l y in a d r e n a l tissue but also in g o n a d a l tissue. 4 Reports o f clinical and h o r m o n a l investigations are c o m m o n in this disorder, 1-9 but to o u r knowledge, those o f a d r e n a l pathology are few e x c e p t for o n e autopsy case t~ a n d o n e case associated with an encapsulated a d r e n a l t u m o r tt c o m p o s e d o f cells with clear cytoplasm. T h e r e f o r e , clinicopathologic analyses, especially d e t a i l e d m o r p h o l o g i c studies, have

From the *Department of Pathology, Tohoku University School of Medicine, Sendai, and the tThird Department of Internal Medicine, Fukushima Medical College, Fukushima, Japan. Accepted for publication 19 November 1986. Dr. Hironobu Sasano's present address is the Department of Pathology, the George Washington University Medical Center, Washington, DC. Address correspondence and reprint requests to Dr. Nobuaki Sasano: Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Sendal 980, Japan. 0046-8177/87 $0.00 + .25

yet to be described. T h i s article describes o u r clinical a n d m o r p h o l o g i c f i n d i n g s in t h r e e cases o f 17aO H D S with i n c i d e n t a l s u r g i c a l r e s e c t i o n o f the a d r e n a l gland.

PATIENTSAND METHODS

Case Reports Case 1. A 21-year-old man was found to have high blood pressure (180/108 mm Hg) at age 20 years. His past and family histories were not remarkable. Three months before the present admission, he was diagnosed as having primary aldosteronism, probably idiopathic hyperaldosteronism because of hypokalemia (3.1 mEq/1), suppressed plasma renin activity, and no radiologic findings suggestive of an adrenocortical tumor. Subsequently, the total left and three quarters of the right adrenal gland were removed for the treatment of idiopathic hyperaldosteronism, especially to control hypertension. Because of persisting hypertension (190/120 mm Hg) and unresponsiveness to spironolactone (300 mg/d) and dexamethasone (2 mg/d) therapy, he was referred to the Fukushima Medical College for further endocrine evaluations. Physical examination on admission revealed high blood pressure (2001140 mm Hg), slight generalized pigmentation of the skin that was prominent in an operative scar in the abdominal wall, and normal male genitalia. General laboratory findings were not remarkable except for hypokalemia (3.3 mEqll) (table 1). Endocrine evaluations (fig. I) revealed increased levels of 17-deoxycorticosteroids, with normal aldosterone, I 1-deoxycortisol, testosterone, and estradiol and decreased dehydroepiandrosterone (DHEA), A4-androstenedione, and 17-hydroxyprogesterone values. Plasma renin activity was suppressed and did not increase after two hours' treatment with furosemide (1 mg/kg) intravenously with the patient in the supine position. The plasma cortisol concentration did not increase significantly (4.42 ~ 4.56 p.g/dl) after metyrapone treatment (0.5 g/d • six doses). Plasma concentrations of A C T H and l l-deoxycorticosterone, serum potassium values, and plasma renin activity as well as blood pressure did not improve after dexamethasone treatment with 3 mg/day for 32 days and 5 mg/day for four weeks, but values did significantly improve after 6 mg/day for six weeks and 8 mg/day for three weeks. During this dexamethasone treatment at 6 rag/day, a 60-minute ACTH test using 1-24 .ACTH, 0.25 mg intravenously, revealed increments of progesterone, l l-deoxycorticosterone, 18-OHdeoxycorticosterone, corticosterone, 18-OH-corticosterone, and PAC but no increases in cortisol, 17-OH-progesterone, 11-deoxycortisoI, and plasma renin activity. An human chorionic gonadotropin test (3000 IUld for three days intramuscularly) revealed the increment of testosterone concentrations (3.79--* 8.78 ng/ml), a luteinizing hormone-releasing hormone test showed hyperresponses of follicle-stimulating hormone and luteinizing hormone,

1002

CONGENITAL 'I7r

DEFICIENCY [Sasano et ol.} cholesterol

A ~ . - - - '!

anglo[ensm~

17-desm.lase

1To- hydroxylase

.

.fl

pregnenotone I @ 25.1 ng/ml( < I ) []

17-hydroxypregnen,)hme 2..~hlg/mlt <51

~

,~,1,~ []

J,hyd,*,,i-

andr,,~terune{I}llEA} (LSI6ng/nit 1 2-7 5)

! r progesterone t

! 17-hydrox)'progesterone ~t~].-~ a~- andrcrstenedkme. I ,~ O.~ng/ml(0.7,1-0.951~ (I,SnglmlUtS-I.5) ",, 21-hydroxylase ~,., ............,.t,,,,.,,.,.,,-,,~........................ ~.........,,,,

f

7.23nglml(O.16-O.42)

i

FIGURE 1. Plasma concentrations of steroid hormones after subtotal adrenalectomy in case I. Values in parentheses are normal ranges. ACTH, adrenocorlicotropic hormone; 'I7-OHCS, 17-hydroxycorticosterolds, 17-KS,t7-ketosteroids.

!

,

t

]

[

corticoslerone(B} ~

I8-hydroxylase

lgAng/mltO.5-lO)

............... 4,,,-.,-............

I

18- hydroxycort ic(~t erone ~ I 67.2ng/dl(4-171 (18 OI[-ID 118 OIi-deh)'drogenase............t " ...............

"-'"-~..

aldosterone ~

3.4-6.3ng/dl(,.O-6.3)

""--....

Urine

pregnandiol 0.3rag/day(0.1 - 0.6)

and a thyrotropin-releasing hormone test (500 ~g intravenously) showed a normal thyrotropin response. Case 2. A 31-year-old genotypic male had a female p h e n o t y p e . His k a r y o t y p e was 46XY. No particular findings were noted in his past and family history. He had been raised as a girl since birth. High blood pressure was noted at age 20 years but was left untreated. At age 30 TABLE 1.

Clinical and Laboratory Findings in Three Cases of 17c~-HydroxyiaseDeficiency Syndrome*

Sex Age Karyotype S e r u m K +, mEq P l a s m a r e n i n activity,

nglml" h Control Supine + furosemide Cortisol, ~tgldl

Case 1

Case 2

Case 3

M 21 46XY 3.3

F 31 46XY 3.0

F 39 46XX 4.3

<0. I <0.I 5.3 (6.3-15.1)

0.14 0.17 6.7 (5-20)

0.4 0.7 0.75 (6.3-15.1)

1 l-Deoxycorticosterone,

nglml

2.26 (0.01-0.2) Aldosterone (rest), nghnl 3.4-6.3 (1.0-6.3) Corticosterone, nglml 19.4 (0.5-10)

3.31 (0.02-0.2) 13.3 (2-13) ...

0.27 (0.02-0.2) 3.41 (1.0-6.3) 35.9 ( 1- 10)

17-OH-progesterone,

nglml

Estradiol,

pghnl

Testosterone, ACTH,

nglml

pglml

0.72 (0.74-0.95) 30.0 (10.0-40.0) 5.4 (4.17-12.0) 620

. . . . . . ...

< 10.0 (10.0-40.0) . . . . . . 211

341

(<100)

(<100)

(<100)

0.8-1.8 (1.6-6.7) 1.4 (2.0-7.6)

3.1 1.76 (4.5-10.2) (1.6-6.7) 3.6 1.2 (3.5--;13.0) (2.0-7.6)

17-OH-corticosterone,

mgld 17-Ketosteroids, mgld

\

ll-de~xycorticosteronelD(X~) ~ 9 9 ,##3\ 11-deoxycontsol(S} "2.26ng/ml(O.Ol-O.2) 11.696ng/mlt 0.2-1.2 ) \ t ilfl-hydroxylase .................,~.............. :..................................... t.............. '

ABBREVIATION: A C T H , a d r e n o c o r t i c o t r o p i c h o r m o n e . * V a l u e s in p a r e n t h e s e s a r e n o r m a l s . 1003

]

'

[ [ I

!/ 1/

/

/ /

/

!

[

lest osterone ~

\'

l

corti~)l(F)

53t,gldl(6.3-15.1)

l

5Ang/ml(,tlT-12.||)

'l~ '~ i

i') i

[

i

1

!

t.~ radiul 4,~ 31LOly.4/ml{10.11--lll.{I)

[ [

i i[

[ l

/

I1

!

f 17-0HCS % pregnantriol ~l' 17-KS 0.8-1.8mg/day(l.6-6.7) <0.01rag/day{02-1.4) 1.4mg/day(2.0-7.6)

years, lie had an episode of mild cerebral hemorrhage. He was referred to Kagoshima University Hospital for further endocrine evaluation. Physical examinations at admission revealed high blood pressure (230-160/130-100 mm Hg), slightly pigmented skin, thin but coarse axillary and pubic hair, small and underdeveloped breast tissue, and female external genitalia. Endocrine findings are shown in table 1. Plasma aldosterone and cortisol values did not increase after a 60minute A C T H test (1-24 ACTH, 0.25 mg intravenously). Urinary pregnanetriol and pregnanediol excretion values were within normal limits. ~q-cholesterol scintigraphy revealed a high uptake in the right adrenal, which was interpreted as showing a right adrenal adenoma. Right adrenalectomy was performed. Clinical and laboratory findings did not improve after the operation, but subsequent dexamethasone treatment at 6 mg/day for three weeks alleviated his elevated blood pressure and other laboratory findings including hypokalemia. Case 3. A 39-year-old woman came to Kobe University Hospital with complaints of general fatigue. Her family history was u n r e m a r k a b l e except for consanguinity (cousins) of her parents. She had no pubertal changes and no menstrual cycle. At age 20 years, high blood pressure of 200/140 m m Hg and hypokalemia of 2.3 mEq/l were noted with hypotonia of her legs. No radiologic evidence of an adrenocortical tumor was found, and she was diagnosed as having idiopathic hyperaldosteronism. Total left and partial right adrenalectomies were performed tO control hypertension and hypokalemia. Since the operation, she had been on corticosteroids treatment, currently hydrocortisone, 20 rag/day orally. Physical examination on admission revealed normal blood pressure (120178 mm Hg); pigmentation in the perioral,region, nails, and cheeks bilaterally; high arched palate'; shield-like thorax, underdeveloped breast tissue; no axillary hair; hypoplastic uterus; and normal female external genitalia with sparce pubic hair. Her serum potassium level was 4.3 mEq/l, probably due to hydrocortisone replacement. Endocrine values at this admission are summarized in table 1. Plasma aldosterone and cortisol values did not increase after the 60-minute A C T H test, and plasma aldosterone and ACTH values were suppressed by dexamethasone, 8 rag/day.

HUMAN PATHOLOGY

Volume 18, No. 10 (October 1987]

Pathologic Examinations

Adrenal tissue for light microscopic examinations was fixed in 10 per cent formalin, made into paraffin sections, and stained with hematoxylineosin, elastica Masson, and Gomori's silver impregnation. Tissue for electron microscopic examinations was fixed in 2 per cent phosphate-buffered gtutaraldehyde and postfixed in 4 per cent cacodylate-buffered osmium tetroxide; tissue was then embedded in epoxy resin, prepared for thin sections, and stained with lead citrate and uranyl acetate. Examinations were performed with a J E O L 100B electron microscope accelerated at 80 kV. For the quantitative evaluation in cases 1 and 2, thickness of corticol layers was measured with a micrometer on a cross section in five parts having tangential features of the fasciculata. Specimens from case 3 were eliminated from the measurement because of the horizontal section. For control measurements, adrenal specimens were used from six patients, aged 32 to 48 years, who had adrenalectomy because of advanced breast cancer. RESULTS Clinical Findings

All three cases of 17e~-OHDS showed high blood pressure, hypokalemia (in case 3, before the first operation and hydrocortisone replacement therapy), increased 1 7 - d e o x y c o r t i c o s t e r o i d s including l ld e o x y c o r t i c o s t e r o n e and corticosterone, elevated A C T H levels, and poor responses of adrenal cortisol secretion to exogenous ACTH. Clinically and hormonally, all three cases improved after dexamethasone treatment. These findings are consistent with those in the cases of 17e~-OHDS reported previously, except that plasma concentrations of aldosterone were elevated in case 2 and normal in cases 1 and 3 a n d the l l - d e o x y c o r t i c o s t e r o n e level was only slightly elevated in case 3. In cases 1 and 2, the cortisol level was slightly low or low-normal, suggestive o f incomplete deficiency o f 17e~-hydroxylase and subsequent compensatory hypersecretion of ACTH.

and reticularis contained few lipid droplets, and their cytoplasm was filled with smooth endoplasmic reticulum and mitochondria with vesicular cristae (fig. 3A). Similar ultrastructural findings were seen in cells of the glomerulosa and outer fasciculata (fig. 3B). Case 2. Grossly, the right adrenal gland was large, weighing 25 g and measuring 7.0 • 8.0 • 1.5 cm. The cortex contained several small nodules. Microscopically, multinodular hyperplasia was evident, and two remarkable nodules measuring 8.5 • 5.0 mm and 6.5 • 3.5 mm were located around the central vein. In these nodules, compact and clear cells with large nuclei were irregularly intermingled, as in the fetal cortex (fig. 4A). In the largest nodule, compact cells were predominant, and foci o f myelolipomatous lesions were observed. In the areas of hypertrophied cells, small lesions of cell infiltration, mainly of lymphocytes mixed with macrophages and rarely with adipose cells suggestive of myelolipomatous lesions, occurred sporadically in the cortex (fig. 4B). Hyperplasia was seemingly prominent in the glomerulosa but contiguously involved by the outer fasciculata (fig. 4C). Nonencapsulated nests of hypertrophic cortical cells and brown adipose tissue were observed in periadrenal adipose tissue. Case 3. T h e right adrenal gland weighed 16.5 g and measured 8 • 3.5 • 0.8 cm; the left weighed 17.5 g and measured 8.5 • 4.0 • 1.0 cm. Histologically, diffuse hyperplasia, mainly composed o f c o r n -

Pathologic Findings in t h e A d r e n a l Glands

Case 1. Grossly, diffuse cortical hyperplasia was particularly evident in the right adrenal (weight, 9.0 g; 3.8 • 3.2 • 1.1 cm). The left gland weighed 5.0 g and measured 3.0 • 3.0 • 0.9 cm. A small, otherwise unremarkable nodule was detectable in both adrenals. Microscopically, slightly hypertrophic compact cells were predominant in the inner fascictflata and reticularis (fig. 2). Clear cells were relatively few in n u m b e r , even in the o u t e r zona fasciculata. A small nodule measuring 3 mm in maximum diameter was observed in the inner zona fasciculata (fig. 2). It was composed of compact and clear cells. Uhrastructurally, cells in the inner fasciculata

FIGURE 2. Adrenocortical hyperplasia in case 1. Slightlyhypertrophic compact cells were abundant in the inner zonae fasciculata and reficularis.The zona glomerulosa was also hyperplastic. (Hematoxylin-eosin stain, x40.)

1004

CONGENITAL 17cx-HYDROXYLASEDEFICIENCY(Sasano et al.)

FIGURE 3. -~ Ultrasfructural findings of compact cells in the hyperplastic inner zonae fasciculata and reticularis shown in figure 2. Most m i t o c h o n d r i a w e r e l a r g e a n d h a d vesicular cristae. Smooth endoplasmic reticula were well developed. Relatively few lipid droplets were observed, and lysosomal droplets were clustered. B, Ultrastructural findings of the outer zona fasciculata cells In case 1. Smooth e n d o plasmic reticula were well developed. Mitochondria were globular and smaller t h a n t h o s e in t h e inner zonae fasciculata and reticuIaris. Mitochondria had vesicular cristae, a n d this type of cristae was generally observed in mitochondria of inner zona fascicul a t a in n o r m a l h u m a n a d r e n a l g l a n d . Similar findings were observed in zona g l o m e r u l o s a cells. [Both, x 13,000.]

pact cells, was remarkable in the fasciculata and reticularis. Large clear cells or cells with large nuclei were scarce. Remarkable myelolipomatous lesions were occasionally observed. Periadrenal cortical nodules composed of compact cells were detected.

Morphometric Evaluations Table 2 shows the width of each cortical layer in the tangential sections with no nodular lesions. In case 1, the zonae fasciculata and reticularis were evidently increased in width. In case 2, the cross section s h o w e d m u l t i n o d u l a r hyperplasia in most part. Therefore, only a limited part, in which the cortex through the medulla was tangentially cut, was subjected to measurement. Grossly, remarkable hyperplasia was seemingly not corroborated by the measurement, but this result was due to sampling error.

DISCUSSION

Decreased secretion o f gtucocorticoids due to 17~-hydroxylase deficiency results in increased secretion o f adrenocorticotropic hormone (ACTH) by the anterior lobe of the pituitary gland. Elevated levels o f plasma A C T H were observed in all three cases o f 17(x-hydroxylase deficiency syndrome (17(xOHDS). As a result of this A C T H excess, the adrenal cortex showed morphologic evidence of hyperstimulation associated with excessive corticosteroid secretion, e.g., diffuse (case 3) and macro- (case 2) or micronodular (case 1) hyperplasia composed mostly of compact cells, periadrenal cortical nodules (cases 2 and 3), and hypertrophied cortical ceils intermingled with dark cells as in the fetal cortex (case 2). Myelolipomatous lesions associated with lymphocyte infiltra-

t005

HUMAN PATHOLOGY

~:~~ ~, "{~ - i ,~','~ . ";k-5.-

Volume 18, No. 10 (October 1987)

.7::? "'.~:-. . . .~. . . . . .". ~::r .

.

.

FIGURE 4. A, Compact cells and clear cells with large nuclei in an adrenocortical nodule in case 2. B, Foci of inflammatory cells suggestive of rnyelolipomatous lesions in the zona fascicuiata in case 2. C, Hyperplasia of the contiguously Involved zona gIomerulosa [n case 2. (A//, hematowlin-eosin stain, x 60.)

tion (cases 2 a n d 3) w e r e i n t e r p r e t e d to be a result o f focal necrosis a n d d e g e n e r a t i o n o f cortical cells d u e to r a p i d t u r n o v e r caused by A C T H stimulation. Such findings o f diffuse cortical h y p e r p l a s i a associated with n o d u l e s w e r e also r e p o r t e d by Morim o t o et al. 1~ in a n a u t o p s y case o f 1 7 a - h y d r o x y l a s e deficiency. T h e s e m o r p h o l o g i c findings a r e similar to t h o s e o f b i l a t e r a l a d r e n o c o r t i c a l h y p e r p l a s i a in C u s h i n g ' s disease, c o n g e n i t a l a d r e n a l h y p e r p l a s i a , a n d o t h e r f o r m s o f A C T H excess s y n d r o m e . A large a d r e n a l m y e l o l i p o m a w e i g h i n g 400 g in a case o f congenital 1 7 a - h y d r o x y l a s e deficiency was described by C o n d o m et al. 12 It is u n c e r t a i n w h e t h e r such a n uncommon tumor developed from a myelolipomatous lesion in the h y p e r p l a s t i c a d r e n a l , as in o u r cases 2 a n d 3, o r w h e t h e r it resulted f r o m m y e l o l i p o m a t o u s t r a n s f o r m a t i o n o f a n a d r e n a l t u m o r w i t h 17c~O H D S . 13 U l t r a s t r u c t u r a l findings in the a d r e n a l g l a n d in

case 1 w e r e n o t significantly d i f f e r e n t f r o m those o f a d r e n o c o r t i c a l h y e r p l a s i a in Cushing's disease; II i.e., cells a b u n d a n t in m i t o c h o n d r i a with vesicular cristae and well-developed smooth endoplasmic reticula w e r e o b s e r v e d in the whole a d r e n a l cortex, particularly in the i n n e r fasciculata, reticularis, a n d n o d u l a r lesions. N o m o r p h o l o g i c abnormalities w e r e o b s e r v e d

TABLE 2.

Thickness of Cortical Layers*

" Glomerulosa Case 1 Case 2 Control

80 94 70 +-- 23

Fasciculata Reticularis 510 310 408 - 54

460 390 280 -z--107

Whole Cortex 1050 794 758 + 156

* Thickness is given in microns. Grossly evident nodules measured 1.5 • 1.0 rnm in case 1 and 8.5 • 5.1mm and 6.5 x 3.5 mm in case 2.

1006

CONGENITAL 17a-HYDROXYLASEDEFICIENCY(Sasano et all

in a d r e n o c o r t i c a l s m o o t h e n d o p l a s m i c r e t i c u l a r , w h e r e 17e~-hydroxylase is located. I n a d r e n o c o r t i c a l h y p e r p l a s i a o f C u s h i n g ' s disease, t h e z o n a g l o m e r u l o s a is usually u n i n v o l v e d by h y p e r p l a s t i c c h a n g e s . I n t h e p r e s e n t cases, h y p e r plasia i n v o l v e d t h e z o n a g l o m e r u l o s a b u t was less evident there. Hypertension, hypokalemia, and renina l d o s t e r o n e s u p p r e s s i o n associated with 1 7 a - O H D S a r e c o n s i d e r e d to be d u e to excessive 1 7 - d e o x y c o r t i c o s t e r o i d s s e c r e t e d by t h e z o n a f a s c i c u l a t a . l - 3,14-19 To explain the suppressed aldosterone secretion, G o l d s m i t h et al. t4 a n d N e w a n d S u v a n n a k u l 7 p r o p o s e d a s o d i u m - r e t a i n i n g effect o f m a r k e d l y elevated 1 1 - d e o x y c o r t i c o s t e r o n e a n d c o r t i c o s t e r o n e secretion f r o m t h e f a s c i c u l a t a , w h i c h in t u r n s u p p r e s s e d p l a s m a r e n i n activity a n d a l d o s t e r o n e s e c r e t i o n by t h e g l o m e r u l o s a ; p r o l o n g e d t r e a t m e n t with d e x a methasone reduced 11-deoxycorticosterone and cort i c o s t e r o n e s e c r e t i o n a n d raised b o t h p l a s m a r e n i n activity a n d a l d o s t e r o n e secretion to n o r m a l values. Also, Biglieri et al. 2~ a n d B e n r a a d et al. 21 d e m o n s t r a t e d t h a t a l d o s t e r o n e secretion was d e c r e a s e d by excessive A C T H s e c r e t i o n . H o w e v e r , in all o f o u r cases o f 17e~-OHDS, p r i o r to d e x a m e t h a s o n e treatm e n t , a l d o s t e r o n e levels w e r e within n o r m a l limits (cases 1 a n d 3) o r s l i g h t l y e l e v a t e d (case 2) a n d p l a s m a r e n i n activity was s u p p r e s s e d ; m o r p h o l o g i c findings corroborated the above endocrinologic findings. T h e d e p e n d e n c y o f t h e z o n a g l o m e r u l o s a o n A C T H as well as o n a l d o s t e r o n e - s t i m u l a t i n g f a c t o r f l 2 [ 3 - e n d o r p h i n , 2s a n d 13-1ipotropin 24 is u n clear, a n d we m u s t await f u r t h e r i n v e s t i g a t i o n s to clarify t h e possible role o f steroid s e c r e t i o n f r o m this morphologically revealed hyperplastic zona glomerulosa in t h e p a t h o p h y s i o l o g y o f 1 7 a - O H D S .

Acknowledgments. T h e authors thank Drs. Fumio Koreeda (Kagoshima University, Kagoshima, Japan) and Kazuo Chihara (Kobe University, Kobe, Japan) for providing the clinical histories to us in cases 2 and 3, respectively; Akio Okura for photographic assistance; and Naoji Haga for electron microscopy study.

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